The co-occurrence of drug use with depression and anxiety (i.e., co-morbidity) disorders is well established, and understanding the complex relationship between these neuropsychiatric disorders is of great therapeutic and prognostic importance. Although most research has focused on adult populations, the initiation into substance use starts during the early years, as reports indicate lifetime drug use rates in adolescents (i.e., children from 8th-12th grades) of 37% for illegal substances and 41% for cigarettes. Adolescence is a critical period during which the brain is still undergoing developmental changes. Because early-life experiences can result in neural plasticity regulating vulnerability to stress/drugs, or predisposition for mental disorders, it is important to characterize the neurobiological consequences of drug exposure during the early years, and how it influences brain pathways to mediate pathological behavior. These studies examine the short- and long-term neurobiological consequences of exposure to nicotine during adolescence in male rats. This proposal studies the role of brain's appetitive neural circuits in the short- and long-term behavioral and biochemical consequences of drug exposure within the proposed developmental rodent model. This approach is novel because it focuses on appetitive regions of the brain (the ventral tegmental area and the nucleus accumbens) important for motivation, reward, and psychomotor activity, and because it focuses on a developmental period where initiation to drug use/abuse and heightened emotional stress often occur. Aim 1 examines whether exposure to nicotine during adolescence influences emotional reactivity using behavioral tests designed to assess an animal's affective state. These include assessing: (a) behavioral reactivity to emotion-eliciting stimuli (open-field, elevated plus-maze, forced swim stress, sucrose preference), (b) natural (sucrose) and (c) drug reward (nicotine and cocaine). Aim 2 assesses the biochemical integrity of this circuit, using basic protein biochemistry, by identifying gene products regulated by exposure to nicotine. Aim 3 determines the functional significance of these nicotine-regulated proteins, using viral vectors, to assess how they influence adolescent brain, resulting in neural adaptations that may increase vulnerability to neuropsychiatric disorders later in adulthood. Data obtained from these studies will improve our understanding of the role drug exposure during adolescence plays in mediating pathological behavior later in life. PUBLIC HEALTH RELEVANCE: The co-occurrence of drug use/abuse with depression and anxiety disorders (i.e., comorbidity) is well established, and understanding the complex relationship between these neuropsychiatric disorders is of great therapeutic and prognostic importance. Because early-life experiences can result in neural plasticity regulating vulnerability to stress/drugs of abuse, and predisposition for mental disorders, it is important to characterize the neurobiological consequences of drug exposure during developmental periods prior to adulthood, and how drug insults influence brain pathways to mediate dysregulated behavior later in life.